Abstract

Targeted activation of pregnane X receptor (PXR) in recent years has become a therapeutic strategy for inflammatory bowel disease (IBD). Chrysin is a naturally occurring flavonoid with anti-inflammation activity. The current study investigated the role of chrysin as a putative mouse PXR agonist in preventing experimental colitis. Pre-administration of chrysin ameliorated inflammatory symptoms in mouse models of colitis (DSS- and TNBS-induced) and resulted in down-regulation of NF-κB target genes (iNOS, ICAM-1, MCP-1, Cox2, TNF-α and IL-6) in the colon mucosa. Chrysin inhibited the phosphorylation/degradation of IκBα, which correlated with the decline in the activity of myeloperoxidase (MPO) and the levels of TNF-α and IL-6 in the colon. Consistent with the in vivo results, chrysin blocked LPS-stimulated nuclear translocation of NF-κB p65 in mouse macrophage RAW264.7. Furthermore, chrysin dose-dependently activated human/mouse PXR in reporter gene assays and up-regulated xenobiotic detoxification genes in the colon mucosa, but not in the liver. Silencing of PXR by RNAi demonstrated necessity of PXR in mediating chrysin's ability to induce xenobiotic detoxification genes and NF-κB inactivation. The repression of NF-κB transcription activity by chrysin was confirmed by in vitro PXR transduction. These findings suggest the effect of chrysin in preventing chemically induced colitis is mediated in large part by a PXR/NF-κB pathway. The data also suggest that chrysin or chrysin-like flavonoids could be further developed as intestine-specific PXR activators.